RARE DISEASE
Meckel syndrome
Meckel syndrome
Meckel syndrome
Synonyms: Dysencephalia splanchnocystica, Meckel-Gruber syndrome
Synonyms: Dysencephalia splanchnocystica, Meckel-Gruber syndrome
Synonyms: Dysencephalia splanchnocystica, Meckel-Gruber syndrome
Drug discovery
81
papers
On emerging therapies
Overview
Meckel syndrome is a lethal autosomal recessive ciliopathy characterized by the triad of occipital encephalocele, cystic renal dysplasia, and postaxial polydactyly. Additional features include hepatic fibrosis, CNS malformations (e.g., holoprosencephaly), and pulmonary hypoplasia. Diagnosis relies on prenatal ultrasound, genetic testing (mutations in MKS1, TMEM67, or other ciliopathy genes), and postmortem findings. Prognosis is uniformly fatal, with most affected pregnancies ending in termination or perinatal death due to multisystem failure [1][6][11][15].
Therapies
No curative treatment exists. Management is palliative, focusing on respiratory support, seizure control, and multisystem care. Genetic counseling is critical for recurrence risk (25%) and prenatal testing in future pregnancies. Surgical interventions (e.g., encephalocele repair) are rarely pursued due to poor prognosis [3][10][12][16].
Categories: rare abdominal surgical diseases, rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare renal diseases, rare surgical maxillo-facial diseases, rare transplant-related disorders
Research Papers
81 drug discovery papers about Meckel syndrome. Recent publications:
81 drug discovery papers about Meckel syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-05-01 | Pharmacokinetics and Therapeutic Effects of an SGK1 Inhibitor in the Tmem67 Rat Model of Hydrocephalus
Disruption of choroid plexus ion transport, barrier integrity, and inflammatory signaling contributes to cerebrospinal fluid (CSF) overproduction and ventriculomegaly in hydrocephalus. Hydrocephalus is a neurological condition characterized by excessive accumulation of CSF within the ventricles, leading to increased ventricular volume and periventricular injury. Surgical intervention, the only current treatment for this disease, works by draining excess CSF from the brain or irreversibly cauterizing the choroid plexus that produces the CSF. It is our hypothesis that pharmaceutical interventions that involved regulation of CSF production would be a less invasive and more scalable option but thus far this approach has not been successful. Our ultimate goal is to identify a treatment that is effective across multiple forms of the disease from pediatric to adult-onset. For this study, we used a congenital hydrocephalus model—the Wistar Polycystic Kidney (WPK) or Transmembrane 67 (Tmem67) rat—which is orthologous to Meckel–Gruber Syndrome type 3 in humans. The Tmem67-/- rat exhibits severe hydrocephalus and demonstrates ciliary dysfunction, and polycystic kidney disease, creating a unique platform for mechanistic and therapeutic investigation. Previously, our laboratory found that SI113, a serum- and glucocorticoid-regulated kinase 1 (SGK1) inhibitor, significantly reduced ventriculomegaly in the Tmem67 rat model of hydrocephalus (Hochstetler et al., 2023). The novelty in the current study is that, instead of solubilizing the compound in dimethyl sulfoxide (DMSO), we used 1-methyl-2-pyrrolidinone (NMP), which may offer a viable alternative since it has been used successfully in clinical studies. Treatment of the animals began on postnatal day 7 (P7) and continued daily until P14. MRI scans were performed before treatment at P7 and after treatment at P15. Wild-type and homozygous animals were divided into several groups: untreated, and those sacrificed 0.5, 2, or 24 hours post-treatment on P15. Results showed that this compound is not only promising in reducing ventriculomegaly, but it was also detectable in the CSF at multiple timepoints. The CSF concentration peaked at the 2-hour timepoint and returned to a level similar to the 0.5 hours timepoint by 24 hours, indicating sustained presence. There was also a measurable compound detected in the plasma for up to 24 hours post-treatment. Together, these findings demonstrate that the compound successfully crosses the blood CSF barrier and blood brain barrier. Western blotting was performed to examine the expression of transient receptor potential vanilloid 4 (TRPV4) and the sodium–potassium–chloride cotransporter 1 (NKCC1), two key transporters in the choroid plexus epithelium that have been implicated in CSF production. The results showed no significant differences in NKCC1 levels, and although TRPV4 was increased at earlier timepoints, it returned to baseline by 24 hours post-treatment. References: Hochstetler AE, et al. (2023) Fluid Barriers CNS 20:61 Funding: Innovator Award from the Hydrocephalus Association and Team Hydro. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-04-02 | TXNDC15 modulated quality control at the endoplasmic reticulum shapes ciliogenesis
SUMMARY At the endoplasmic reticulum (ER), membrane protein quality control is tightly regulated to ensure excess subunits are recognized and degraded to protect cellular homeostasis. Using genome wide CRISPR screens, we identified a factor of unknown function, thioredoxin domain containing protein 15 (TXNDC15), and showed that it regulates membrane protein stability by tuning the activity of the E3-ubiquitin ligase, MARCHF6. TXNDC15 modulates MARCHF6 in two opposing ways: first, it enhances the binding, ubiquitination, and degradation of membrane protein subunits with soluble cytosolic domains; and second, it prevents the inappropriate recruitment and ubiquitination of subunits with globular lumenal domains. Patient mutations to TXNDC15 that cause the ciliopathy Meckel-Gruber syndrome, disrupted its binding to MARCHF6, allowing degradation of critical ciliary proteins as they transit through the ER leading to defects in ciliogenesis. The regulatory function of TXNDC15 therefore exemplifies how protein quality control maintains the integrity of the proteome to prevent disease.
2025-11-10 | Primary cilia in neural development and disease.
The Primary cilium, a non-motile organelle, was long underestimated but has recently been recognized as a pivotal signaling platform in nervous system development. This review summarizes the structural features, biogenesis, and dynamic regulation of primary cilia, and systematically examines their roles in neural stem cells fate determination, neurogenesis, neuronal migration, axon guidance, and synaptogenesis. By integrating multiple developmental signaling pathways, including Sonic hedgehog, Wnt, Notch, and mTOR, primary cilia orchestrate the precise spatiotemporal patterning of the nervous system. Dysfunction of primary cilia is closely linked to a wide spectrum of neurodevelopmental disorders, ranging from classical ciliopathies such as Meckel-Gruber syndrome, Joubert syndrome, and Bardet-Biedl syndrome, to complex conditions such as autism spectrum disorder, schizophrenia, and bipolar disorder, all of which can be traced to ciliary signaling imbalances. This paper introduces the concept of the continuous spectrum of Ciliogenesis, in which phenotypes from severe structural malformations to subtle functional abnormalities can be attributed to defects in specific ciliary modules. Future interventions, including organoid models, super-resolution imaging, and cilia-targeted therapeutic strategies, hold promise for advancing pathological insights and developing novel treatments for neurodevelopmental disorders.
2022-05-20 | Septin-Mediated RhoA Activation Engages the Exocyst Complex to Recruit the Cilium Transition Zone
ABSTRACT Septins are filamentous GTPases that play important, but poorly characterized roles in ciliogenesis. Here, we show that SEPTIN9 regulates RhoA signaling at the base of cilia by binding and activating the RhoA guanine nucleotide exchange factor, ARHGEF18. GTP-RhoA is known to activate the membrane targeting exocyst complex, and suppression of SEPTIN9 causes disruption of ciliogenesis and mislocalization of an exocyst subunit, SEC8. Using basal body-targeted proteins we show that upregulating RhoA signaling at the cilium can rescue ciliary defects and mislocalization of SEC8 caused by global SEPTIN9 depletion. Moreover, we demonstrate that transition zone components, RPGRIP1L and TCTN2 fail to accumulate at the transition zone in cells lacking SEPTIN9 or depleted of the exocyst complex. Thus, SEPTIN9 regulates the recruitment of transition zone proteins on Golgi-derived vesicles by activating the exocyst via RhoA to allow the formation of primary cilia.
2021-09-01 | CEP55 promotes cilia disassembly through stabilizing Aurora A kinase.
Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55-/- mice display clinical manifestations of Meckel-Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55-/- mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel-Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.
proteins
2025-05-29 | Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis.
TMEM67 mutations cause Meckel-Gruber syndrome and other related ciliopathies. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: a C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67-/- mice, but in contrast, transduces normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.
2024-09-17 | Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis.
TMEM67 mutations are the major cause of Meckel-Gruber syndrome. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a novel cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: A C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a novel non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67 -/- mice, but in contrast, undergo normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.
2024-05-16 | Defects in diffusion barrier function of ciliary transition zone caused by ciliopathy variations of TMEM218.
Primary cilia are antenna-like structures protruding from the surface of various eukaryotic cells, and have distinct protein compositions in their membranes. This distinct protein composition is maintained by the presence of the transition zone (TZ) at the ciliary base, which acts as a diffusion barrier between the ciliary and plasma membranes. Defects in cilia and the TZ are known to cause a group of disorders collectively called the ciliopathies, which demonstrate a broad spectrum of clinical features, such as perinatally lethal Meckel syndrome (MKS), relatively mild Joubert syndrome (JBTS), and nonsyndromic nephronophthisis (NPHP). Proteins constituting the TZ can be grouped into the MKS and NPHP modules. The MKS module is composed of several transmembrane proteins and three soluble proteins. TMEM218 was recently reported to be mutated in individuals diagnosed as MKS and JBTS. However, little is known about how TMEM218 mutations found in MKS and JBTS affect the functions of cilia. In this study, we found that ciliary membrane proteins were not localized to cilia in TMEM218-knockout cells, indicating impaired barrier function of the TZ. Furthermore, the exogenous expression of JBTS-associated TMEM218 variants but not MKS-associated variants in TMEM218-knockout cells restored the localization of ciliary membrane proteins. In particular, when expressed in TMEM218-knockout cells, the TMEM218(R115H) variant found in JBTS was able to restore the barrier function of cells, whereas the MKS variant TMEM218(R115C) could not. Thus, the severity of symptoms of MKS and JBTS individuals appears to correlate with the degree of their ciliary defects at the cellular level.
2022-01-03 | Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses
Abstract Meckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.
2015-07-13 | Rescue of corpus callosum agenesis in two ciliary mutants by the short repressor isoform of Gli3
Agenesis of the Corpus callosum (AgCC) is a frequent brain disorder found in over 50 human congenital syndromes including ciliopathies.Here, we report a severe AgCC in Ftm/Rpgrip1l knock-out mice, which provide a valuable model for Meckel-Grüber syndrome.Ftm encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in some, but not all cell types in mice, including neuroepithelial cells in the developing forebrain.We show that AgCC in Ftm -/-fetuses results from a mislocalization of guidepost cells in the dorsomedial telencephalon and not from a reduction of callosal neurons in the cortex.This abnormal distribution of the guideposts primarily results from patterning defects in the medial telencephalon, which relies on Gli3 processing defects.These patterning defects, mispositioning of dorsomedial guideposts and AgCC can all be rescued by reintroducing Gli3R in Ftm -/-embryos, provided by the Gli3D699 allele, which produces only the short repressor isoform of Gli3.This rescue of AgCC of Ftm -/-mutants by one allele of Gli3D699 confirms and completes our knowledge on the pre-eminent role of Gli3 in CC formation.Furthermore, Gli3D699 also rescue AgCC in Rfx3 -/- mutant, another ciliary mutant deficient for a transcription factor controlling several ciliary genes.Rescuing the CC formation in two independent ciliary mutants by a single molecule, namely Gli3R, highlight the crucial role of primary cilia in maintaining the proper level of Gli3R required for CC morphogenesis.These data demonstrate that Gli3 processing is the major outcome of primary cilia function in CC formation.
gene therapies
2026-03-20 | Meckel-Gruber syndrome: a rare and fatal congenital disorder (case report).
Meckel-Gruber syndrome is a rare congenital disorder characterized by multiple malformations. It transmits via a recessive autosomal mode. It is characterized by an occipital encephalocele, polydactyly, and polycystic renal dysplasia. The diagnosis could be established via ultrasound. In fact, it is actually the key method for the early screening of this lethal malformation with at least two of its main characteristics. However, the diagnosis is confirmed by karyotype analysis. Herein, we present a case of Meckel-Gruber syndrome diagnosed in a fetus from a consanguineous marriage in a 40-year-old woman, gravida 2 para 1, with one previous healthy child. This pregnancy was terminated at 19 weeks of gestation. The diagnosis was made through prenatal ultrasound and magnetic resonance imaging (MRI). With later confirmation by fetal autopsy.
2026-02-04 | Meckel-Gruber syndrome: A case report
Meckel–Gruber syndrome (MGS) is a rare, lethal, autosomal recessive ciliopathy characterized classically by a triad of central nervous system malformations, postaxial polydactyly, and renal cystic dysplasia. The condition is associated with a poor prognosis, and early antenatal diagnosis plays a crucial role in parental counseling and pregnancy management. However, considerable phenotypic variability exists, and incomplete expression of the classical triad has been reported in a minority of cases. We report a case of MGS with an atypical presentation. A term male neonate was born to a 21-year-old mother from a non-consanguineous marriage. First- and early second-trimester antenatal ultrasonography scans were reported as normal. A third-trimester ultrasound revealed abnormalities suggestive of a congenital malformation. At birth, the neonate was noted to have an occipital encephalocele and postaxial polydactyly. Notably, renal involvement was absent, which is an uncommon finding in MGS. The diagnosis was established based on characteristic clinical features and imaging findings. This case highlights the phenotypic variability of MGS and emphasizes that absence of renal cystic dysplasia does not exclude the diagnosis. It also underlines the importance of detailed and serial antenatal imaging, particularly in pregnancies without early ultrasound abnormalities. Given the autosomal recessive inheritance pattern of MGS and a recurrence risk of 25% in subsequent pregnancies, early diagnosis is essential for appropriate genetic counseling and informed decision-making. Reporting such atypical presentations expands the existing knowledge of the clinical spectrum of MGS and reinforces the need for heightened clinical suspicion even when all components of the classical triad are not present.
2026-01-10 | CRISPR-Cas9-Generated TXNDC15 c.560delA Homozygous Mouse Model Exhibits Meckel-Gruber Syndrome Phenotype.
To determine whether TXNDC15 variation causes Meckel-Gruber syndrome (MKS), we assessed the pathogenicity of the frameshift variant c.560delA. A CRISPR-Cas9 generated mouse model carrying the equivalent Txndc15 c.512delA mutation was analyzed at embryonic day 15.5. Homozygous Txndc15mt/mt embryos displayed the complete MKS phenotype-fetal lethality, exencephaly, omphalocele, post-axial polydactyly, and polycystic kidneys-together with markedly reduced TXNDC15 protein in brain, liver, and kidney. These findings confirm TXNDC15 as a bona fide MKS disease gene.
2025-12-30 | Advances in Prenatal Diagnosis and Genetic Research of Ciliopathies
Primary cilium is a kind of organelle that widely exists on the surface of various cells. It is small but complex in structure and has powerful effects. Cilia defects often lead to a series of disorders that are collectively termed “ciliopathies,” involving multiple systems. In recent years, it has been found that defects in ciliary morphology and function can lead to genetic diseases in newborns. Since cilia play a rather important role in regulating the balance of development and internal environment in vertebrates, the loss of genes related to cilia is associated with a range of diseases. Prenatal detection of renal abnormalities associated with skeletal or cerebral abnormalities should raise suspicion of multisystem ciliopathy, which is often associated with a variety of syndromes, including Meckel-Gruber syndrome, Joubert syndrome, Nephronophthisis, and Bardet-Biedl syndrome. Combined with recent studies, this article mainly summarizes four categories of cilia-related diseases in order to provide references for clinical diagnosis.
2025-12-11 | Meckel-Gruber Syndrome due to Homozygous c.16del (p.Leu6SerfsTer15) Variant in the TCTN1: First Case from Türkiye.
Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Almost all of them are lethal in the prenatal or first postnatal periods. It is usually diagnosed clinically with a detailed prenatal ultrasound examination. Variants have been reported in at least 14 different genes. We report a male fetus with oligohydramnios, large kidneys with microcysts covering the entire abdomen, postaxial polydactyly of the hands, bilateral pes equinovarus, encephalocele, microphthalmia, short extremities, and a mass lesion under the diaphragm. Termination was recommended to the family due to severe findings. Fetal skin biopsy and parental peripheral blood samples were obtained to investigate the potential pathogenic variants associated with MKS via clinical exome sequencing and Sanger sequencing. The fetus was homozygous for the c.16del (p.Leu6SerfsTer15) variant in the TCTN1 (NM_001082538.3), and both parents were heterozygous for the variant. Genetic diagnosis is very important in terms of counseling for subsequent pregnancies. To our knowledge, this is the third Meckel-Gruber case in the literature caused by the TCTN1, and a novel likely pathogenic variant was detected.
oligonucleotides
2022-03-23 | Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.
Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue-specific preservation of the amount of expressed functional protein. We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120- and CC2D2A-associated disease and we combined in silico and ex vivo approaches to study tissue-specific transcripts and identify molecular targets for exon skipping. We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. Genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.
2011-01-05 | Disruption of planar cell polarity activity leads to developmental biliary defects
Planar cell polarity (PCP) establishes polarity within an epithelial sheet. Defects in PCP are associated with developmental defects involving directional cell growth, including defects in kidney tubule elongation that lead to formation of kidney cysts. Given the strong association between kidney cyst formation and developmental biliary defects in patients and in animal models, we investigated the importance of PCP in biliary development. Here we report that in zebrafish, morpholino antisense oligonucleotide-mediated knockdown of PCP genes including prickle-1a (pk1a) led to developmental biliary abnormalities, as well as localization defects of the liver and other digestive organs. The defects in biliary development appear to be mediated via downstream PCP targets such as Rho kinase, Jun kinase (JNK), and both actin and microtubule components of the cytoskeleton. Knockdown of pk1a led to decreased expression of vhnf1, a homeodomain gene previously shown to be involved in biliary development and in kidney cyst formation; forced expression of vhnf1 mRNA led to rescue of the pk1a morphant phenotype. Our results demonstrate that PCP plays an important role in vertebrate biliary development, interacting with other factors known to be involved in biliary morphogenesis.
small molecules
2026-05-01 | Pharmacokinetics and Therapeutic Effects of an SGK1 Inhibitor in the Tmem67 Rat Model of Hydrocephalus
Disruption of choroid plexus ion transport, barrier integrity, and inflammatory signaling contributes to cerebrospinal fluid (CSF) overproduction and ventriculomegaly in hydrocephalus. Hydrocephalus is a neurological condition characterized by excessive accumulation of CSF within the ventricles, leading to increased ventricular volume and periventricular injury. Surgical intervention, the only current treatment for this disease, works by draining excess CSF from the brain or irreversibly cauterizing the choroid plexus that produces the CSF. It is our hypothesis that pharmaceutical interventions that involved regulation of CSF production would be a less invasive and more scalable option but thus far this approach has not been successful. Our ultimate goal is to identify a treatment that is effective across multiple forms of the disease from pediatric to adult-onset. For this study, we used a congenital hydrocephalus model—the Wistar Polycystic Kidney (WPK) or Transmembrane 67 (Tmem67) rat—which is orthologous to Meckel–Gruber Syndrome type 3 in humans. The Tmem67-/- rat exhibits severe hydrocephalus and demonstrates ciliary dysfunction, and polycystic kidney disease, creating a unique platform for mechanistic and therapeutic investigation. Previously, our laboratory found that SI113, a serum- and glucocorticoid-regulated kinase 1 (SGK1) inhibitor, significantly reduced ventriculomegaly in the Tmem67 rat model of hydrocephalus (Hochstetler et al., 2023). The novelty in the current study is that, instead of solubilizing the compound in dimethyl sulfoxide (DMSO), we used 1-methyl-2-pyrrolidinone (NMP), which may offer a viable alternative since it has been used successfully in clinical studies. Treatment of the animals began on postnatal day 7 (P7) and continued daily until P14. MRI scans were performed before treatment at P7 and after treatment at P15. Wild-type and homozygous animals were divided into several groups: untreated, and those sacrificed 0.5, 2, or 24 hours post-treatment on P15. Results showed that this compound is not only promising in reducing ventriculomegaly, but it was also detectable in the CSF at multiple timepoints. The CSF concentration peaked at the 2-hour timepoint and returned to a level similar to the 0.5 hours timepoint by 24 hours, indicating sustained presence. There was also a measurable compound detected in the plasma for up to 24 hours post-treatment. Together, these findings demonstrate that the compound successfully crosses the blood CSF barrier and blood brain barrier. Western blotting was performed to examine the expression of transient receptor potential vanilloid 4 (TRPV4) and the sodium–potassium–chloride cotransporter 1 (NKCC1), two key transporters in the choroid plexus epithelium that have been implicated in CSF production. The results showed no significant differences in NKCC1 levels, and although TRPV4 was increased at earlier timepoints, it returned to baseline by 24 hours post-treatment. References: Hochstetler AE, et al. (2023) Fluid Barriers CNS 20:61 Funding: Innovator Award from the Hydrocephalus Association and Team Hydro. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2026-04-02 | TXNDC15 modulated quality control at the endoplasmic reticulum shapes ciliogenesis
SUMMARY At the endoplasmic reticulum (ER), membrane protein quality control is tightly regulated to ensure excess subunits are recognized and degraded to protect cellular homeostasis. Using genome wide CRISPR screens, we identified a factor of unknown function, thioredoxin domain containing protein 15 (TXNDC15), and showed that it regulates membrane protein stability by tuning the activity of the E3-ubiquitin ligase, MARCHF6. TXNDC15 modulates MARCHF6 in two opposing ways: first, it enhances the binding, ubiquitination, and degradation of membrane protein subunits with soluble cytosolic domains; and second, it prevents the inappropriate recruitment and ubiquitination of subunits with globular lumenal domains. Patient mutations to TXNDC15 that cause the ciliopathy Meckel-Gruber syndrome, disrupted its binding to MARCHF6, allowing degradation of critical ciliary proteins as they transit through the ER leading to defects in ciliogenesis. The regulatory function of TXNDC15 therefore exemplifies how protein quality control maintains the integrity of the proteome to prevent disease.
2025-11-10 | Primary cilia in neural development and disease.
The Primary cilium, a non-motile organelle, was long underestimated but has recently been recognized as a pivotal signaling platform in nervous system development. This review summarizes the structural features, biogenesis, and dynamic regulation of primary cilia, and systematically examines their roles in neural stem cells fate determination, neurogenesis, neuronal migration, axon guidance, and synaptogenesis. By integrating multiple developmental signaling pathways, including Sonic hedgehog, Wnt, Notch, and mTOR, primary cilia orchestrate the precise spatiotemporal patterning of the nervous system. Dysfunction of primary cilia is closely linked to a wide spectrum of neurodevelopmental disorders, ranging from classical ciliopathies such as Meckel-Gruber syndrome, Joubert syndrome, and Bardet-Biedl syndrome, to complex conditions such as autism spectrum disorder, schizophrenia, and bipolar disorder, all of which can be traced to ciliary signaling imbalances. This paper introduces the concept of the continuous spectrum of Ciliogenesis, in which phenotypes from severe structural malformations to subtle functional abnormalities can be attributed to defects in specific ciliary modules. Future interventions, including organoid models, super-resolution imaging, and cilia-targeted therapeutic strategies, hold promise for advancing pathological insights and developing novel treatments for neurodevelopmental disorders.
2022-05-20 | Septin-Mediated RhoA Activation Engages the Exocyst Complex to Recruit the Cilium Transition Zone
ABSTRACT Septins are filamentous GTPases that play important, but poorly characterized roles in ciliogenesis. Here, we show that SEPTIN9 regulates RhoA signaling at the base of cilia by binding and activating the RhoA guanine nucleotide exchange factor, ARHGEF18. GTP-RhoA is known to activate the membrane targeting exocyst complex, and suppression of SEPTIN9 causes disruption of ciliogenesis and mislocalization of an exocyst subunit, SEC8. Using basal body-targeted proteins we show that upregulating RhoA signaling at the cilium can rescue ciliary defects and mislocalization of SEC8 caused by global SEPTIN9 depletion. Moreover, we demonstrate that transition zone components, RPGRIP1L and TCTN2 fail to accumulate at the transition zone in cells lacking SEPTIN9 or depleted of the exocyst complex. Thus, SEPTIN9 regulates the recruitment of transition zone proteins on Golgi-derived vesicles by activating the exocyst via RhoA to allow the formation of primary cilia.
2021-09-01 | CEP55 promotes cilia disassembly through stabilizing Aurora A kinase.
Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55-/- mice display clinical manifestations of Meckel-Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55-/- mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel-Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.
proteins
2025-05-29 | Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis.
TMEM67 mutations cause Meckel-Gruber syndrome and other related ciliopathies. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: a C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67-/- mice, but in contrast, transduces normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.
2024-09-17 | Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis.
TMEM67 mutations are the major cause of Meckel-Gruber syndrome. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a novel cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: A C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three TMEM67 ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and C. elegans, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a novel non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying Tmem67 -/- mice, but in contrast, undergo normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.
2024-05-16 | Defects in diffusion barrier function of ciliary transition zone caused by ciliopathy variations of TMEM218.
Primary cilia are antenna-like structures protruding from the surface of various eukaryotic cells, and have distinct protein compositions in their membranes. This distinct protein composition is maintained by the presence of the transition zone (TZ) at the ciliary base, which acts as a diffusion barrier between the ciliary and plasma membranes. Defects in cilia and the TZ are known to cause a group of disorders collectively called the ciliopathies, which demonstrate a broad spectrum of clinical features, such as perinatally lethal Meckel syndrome (MKS), relatively mild Joubert syndrome (JBTS), and nonsyndromic nephronophthisis (NPHP). Proteins constituting the TZ can be grouped into the MKS and NPHP modules. The MKS module is composed of several transmembrane proteins and three soluble proteins. TMEM218 was recently reported to be mutated in individuals diagnosed as MKS and JBTS. However, little is known about how TMEM218 mutations found in MKS and JBTS affect the functions of cilia. In this study, we found that ciliary membrane proteins were not localized to cilia in TMEM218-knockout cells, indicating impaired barrier function of the TZ. Furthermore, the exogenous expression of JBTS-associated TMEM218 variants but not MKS-associated variants in TMEM218-knockout cells restored the localization of ciliary membrane proteins. In particular, when expressed in TMEM218-knockout cells, the TMEM218(R115H) variant found in JBTS was able to restore the barrier function of cells, whereas the MKS variant TMEM218(R115C) could not. Thus, the severity of symptoms of MKS and JBTS individuals appears to correlate with the degree of their ciliary defects at the cellular level.
2022-01-03 | Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses
Abstract Meckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.
2015-07-13 | Rescue of corpus callosum agenesis in two ciliary mutants by the short repressor isoform of Gli3
Agenesis of the Corpus callosum (AgCC) is a frequent brain disorder found in over 50 human congenital syndromes including ciliopathies.Here, we report a severe AgCC in Ftm/Rpgrip1l knock-out mice, which provide a valuable model for Meckel-Grüber syndrome.Ftm encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in some, but not all cell types in mice, including neuroepithelial cells in the developing forebrain.We show that AgCC in Ftm -/-fetuses results from a mislocalization of guidepost cells in the dorsomedial telencephalon and not from a reduction of callosal neurons in the cortex.This abnormal distribution of the guideposts primarily results from patterning defects in the medial telencephalon, which relies on Gli3 processing defects.These patterning defects, mispositioning of dorsomedial guideposts and AgCC can all be rescued by reintroducing Gli3R in Ftm -/-embryos, provided by the Gli3D699 allele, which produces only the short repressor isoform of Gli3.This rescue of AgCC of Ftm -/-mutants by one allele of Gli3D699 confirms and completes our knowledge on the pre-eminent role of Gli3 in CC formation.Furthermore, Gli3D699 also rescue AgCC in Rfx3 -/- mutant, another ciliary mutant deficient for a transcription factor controlling several ciliary genes.Rescuing the CC formation in two independent ciliary mutants by a single molecule, namely Gli3R, highlight the crucial role of primary cilia in maintaining the proper level of Gli3R required for CC morphogenesis.These data demonstrate that Gli3 processing is the major outcome of primary cilia function in CC formation.
gene therapies
2026-03-20 | Meckel-Gruber syndrome: a rare and fatal congenital disorder (case report).
Meckel-Gruber syndrome is a rare congenital disorder characterized by multiple malformations. It transmits via a recessive autosomal mode. It is characterized by an occipital encephalocele, polydactyly, and polycystic renal dysplasia. The diagnosis could be established via ultrasound. In fact, it is actually the key method for the early screening of this lethal malformation with at least two of its main characteristics. However, the diagnosis is confirmed by karyotype analysis. Herein, we present a case of Meckel-Gruber syndrome diagnosed in a fetus from a consanguineous marriage in a 40-year-old woman, gravida 2 para 1, with one previous healthy child. This pregnancy was terminated at 19 weeks of gestation. The diagnosis was made through prenatal ultrasound and magnetic resonance imaging (MRI). With later confirmation by fetal autopsy.
2026-02-04 | Meckel-Gruber syndrome: A case report
Meckel–Gruber syndrome (MGS) is a rare, lethal, autosomal recessive ciliopathy characterized classically by a triad of central nervous system malformations, postaxial polydactyly, and renal cystic dysplasia. The condition is associated with a poor prognosis, and early antenatal diagnosis plays a crucial role in parental counseling and pregnancy management. However, considerable phenotypic variability exists, and incomplete expression of the classical triad has been reported in a minority of cases. We report a case of MGS with an atypical presentation. A term male neonate was born to a 21-year-old mother from a non-consanguineous marriage. First- and early second-trimester antenatal ultrasonography scans were reported as normal. A third-trimester ultrasound revealed abnormalities suggestive of a congenital malformation. At birth, the neonate was noted to have an occipital encephalocele and postaxial polydactyly. Notably, renal involvement was absent, which is an uncommon finding in MGS. The diagnosis was established based on characteristic clinical features and imaging findings. This case highlights the phenotypic variability of MGS and emphasizes that absence of renal cystic dysplasia does not exclude the diagnosis. It also underlines the importance of detailed and serial antenatal imaging, particularly in pregnancies without early ultrasound abnormalities. Given the autosomal recessive inheritance pattern of MGS and a recurrence risk of 25% in subsequent pregnancies, early diagnosis is essential for appropriate genetic counseling and informed decision-making. Reporting such atypical presentations expands the existing knowledge of the clinical spectrum of MGS and reinforces the need for heightened clinical suspicion even when all components of the classical triad are not present.
2026-01-10 | CRISPR-Cas9-Generated TXNDC15 c.560delA Homozygous Mouse Model Exhibits Meckel-Gruber Syndrome Phenotype.
To determine whether TXNDC15 variation causes Meckel-Gruber syndrome (MKS), we assessed the pathogenicity of the frameshift variant c.560delA. A CRISPR-Cas9 generated mouse model carrying the equivalent Txndc15 c.512delA mutation was analyzed at embryonic day 15.5. Homozygous Txndc15mt/mt embryos displayed the complete MKS phenotype-fetal lethality, exencephaly, omphalocele, post-axial polydactyly, and polycystic kidneys-together with markedly reduced TXNDC15 protein in brain, liver, and kidney. These findings confirm TXNDC15 as a bona fide MKS disease gene.
2025-12-30 | Advances in Prenatal Diagnosis and Genetic Research of Ciliopathies
Primary cilium is a kind of organelle that widely exists on the surface of various cells. It is small but complex in structure and has powerful effects. Cilia defects often lead to a series of disorders that are collectively termed “ciliopathies,” involving multiple systems. In recent years, it has been found that defects in ciliary morphology and function can lead to genetic diseases in newborns. Since cilia play a rather important role in regulating the balance of development and internal environment in vertebrates, the loss of genes related to cilia is associated with a range of diseases. Prenatal detection of renal abnormalities associated with skeletal or cerebral abnormalities should raise suspicion of multisystem ciliopathy, which is often associated with a variety of syndromes, including Meckel-Gruber syndrome, Joubert syndrome, Nephronophthisis, and Bardet-Biedl syndrome. Combined with recent studies, this article mainly summarizes four categories of cilia-related diseases in order to provide references for clinical diagnosis.
2025-12-11 | Meckel-Gruber Syndrome due to Homozygous c.16del (p.Leu6SerfsTer15) Variant in the TCTN1: First Case from Türkiye.
Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Almost all of them are lethal in the prenatal or first postnatal periods. It is usually diagnosed clinically with a detailed prenatal ultrasound examination. Variants have been reported in at least 14 different genes. We report a male fetus with oligohydramnios, large kidneys with microcysts covering the entire abdomen, postaxial polydactyly of the hands, bilateral pes equinovarus, encephalocele, microphthalmia, short extremities, and a mass lesion under the diaphragm. Termination was recommended to the family due to severe findings. Fetal skin biopsy and parental peripheral blood samples were obtained to investigate the potential pathogenic variants associated with MKS via clinical exome sequencing and Sanger sequencing. The fetus was homozygous for the c.16del (p.Leu6SerfsTer15) variant in the TCTN1 (NM_001082538.3), and both parents were heterozygous for the variant. Genetic diagnosis is very important in terms of counseling for subsequent pregnancies. To our knowledge, this is the third Meckel-Gruber case in the literature caused by the TCTN1, and a novel likely pathogenic variant was detected.
oligonucleotides
2022-03-23 | Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.
Mutations in ciliary genes cause a spectrum of both overlapping and distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic examples for this genetic heterogeneity and pleiotropy as mutations in both cause Joubert syndrome but are also associated with skeletal ciliopathies and Meckel syndrome, respectively. The molecular basis for this phenotypical variability is not understood but basal exon skipping likely contributes to tolerance for deleterious mutations via tissue-specific preservation of the amount of expressed functional protein. We systematically reviewed and annotated genetic variants and clinical presentations reported in CEP120- and CC2D2A-associated disease and we combined in silico and ex vivo approaches to study tissue-specific transcripts and identify molecular targets for exon skipping. We confirmed more severe clinical presentations associated with truncating CC2D2A mutations. We identified and confirmed basal exon skipping in the kidney, with possible relevance for organ-specific disease manifestations. Finally, we proposed a multimodal approach to classify exons amenable to exon skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A exons were identified as potentially rescuable by targeted exon skipping, an approach that is already in clinical use for other inherited human diseases. Genotype-phenotype correlations for CC2D2A support the deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for therapeutic exon skipping approaches.
2011-01-05 | Disruption of planar cell polarity activity leads to developmental biliary defects
Planar cell polarity (PCP) establishes polarity within an epithelial sheet. Defects in PCP are associated with developmental defects involving directional cell growth, including defects in kidney tubule elongation that lead to formation of kidney cysts. Given the strong association between kidney cyst formation and developmental biliary defects in patients and in animal models, we investigated the importance of PCP in biliary development. Here we report that in zebrafish, morpholino antisense oligonucleotide-mediated knockdown of PCP genes including prickle-1a (pk1a) led to developmental biliary abnormalities, as well as localization defects of the liver and other digestive organs. The defects in biliary development appear to be mediated via downstream PCP targets such as Rho kinase, Jun kinase (JNK), and both actin and microtubule components of the cytoskeleton. Knockdown of pk1a led to decreased expression of vhnf1, a homeodomain gene previously shown to be involved in biliary development and in kidney cyst formation; forced expression of vhnf1 mRNA led to rescue of the pk1a morphant phenotype. Our results demonstrate that PCP plays an important role in vertebrate biliary development, interacting with other factors known to be involved in biliary morphogenesis.
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